tbuckley/cabot-search huggingface dataset:
Host-versus-commensal immune responses participate in the rejection of colonized solid organ transplants
Authors: Isabella Pirozzolo, Martin Sepulveda, Luqiu Chen, Ying Wang, Yuk Man Lei, Zhipeng Li, Rena Li, Husain Sattar, Betty Theriault, Yasmine Belkaid, Anita S. Chong, Maria-Luisa Alegre
Journal: Journal of Clinical Investigation (2022)

Solid organ transplantation is the preferred treatment for end-stage organ failure. Although transplant recipients take life-long immunosuppressive drugs, a substantial percentage of them still reject their allografts. Strikingly, barrier organs colonized with microbiota have significantly shorter half-lives than non-barrier transplanted organs, even in immunosuppressed hosts. We previously demonstrated that skin allografts monocolonized with the common human commensal Staphylococcus epidermidis (S.epi) are rejected faster than germ-free (GF) allografts in mice because the presence of S.epi augments the effector alloimmune response locally in the graft. Here, we tested whether host immune responses against graft-resident commensal microbes, including S.epi, can damage colonized grafts independently from the alloresponse. Naive hosts mounted an anticommensal T cell response to colonized, but not GF, syngeneic skin grafts. Whereas naive antigraft commensal T cells modestly damaged colonized syngeneic skin grafts, hosts with prior anticommensal T cell memory mounted a post-transplant immune response against graft-resident commensals that significantly damaged colonized, syngeneic skin grafts. Importantly, allograft recipients harboring this host-versus-commensal immune response resisted immunosuppression. The dual effects of host-versus-commensal and host-versus-allograft responses may partially explain why colonized organs have poorer outcomes than sterile organs in the clinic.
GITR Antibodies in Cancer: Not Ready for Prime Time
Authors: Tatiana Hernandez-Guerrero, Victor Moreno
Journal: Clinical Cancer Research (2022)

Summary Glucocorticoid-induced TNF receptor (TNFR)-related protein (GITR) agonistic antibodies are expected to increase the antitumor response mainly by reducing the effect of Foxp3+ T-regulatory cells. TRX-518 is a novel GITR agonist that has shown good pharmacodynamic activity by depleting regulatory T cells (Tregs) in preclinical models, with limited clinical activity demonstrated in patients with advanced solid tumors. See related article by Davar et al., p. 3990
Allosteric activation of the metabolic enzyme GPD1 inhibits bladder cancer growth via the lysoPC-PAFR-TRPV2 axis
Authors: Wenlong Zhang, Xin He, Haoli Yin, Wenmin Cao, Tingsheng Lin, Wei Chen, Wenli Diao, Meng Ding, Hao Hu, Wenjing Mo, Qing Zhang, Hongqian Guo
Journal: Journal of Hematology & Oncology (2022)

Abstract Background Bladder cancer is the most common malignant tumor of the urinary system. Surgical resection and chemotherapy are the two mainstream treatments for bladder cancer. However, the outcomes are not satisfactory for patients with advanced bladder cancer. There is a need to further explore more effective targeted therapeutic strategies. Methods Proteomics were performed to compare protein expression differences between human bladder cancer tissues and adjacent normal tissues. The function of GPD1 on bladder cancer cells were confirmed through in vivo and in vitro assays. Transcriptomics and metabolomics were performed to reveal the underlying mechanisms of GPD1. Virtual screening was used to identify allosteric activator of GPD1. Results Here, we used proteomics to find that GPD1 expression was at low levels in bladder cancer tissues. Further investigation showed that GPD1 overexpression significantly promoted apoptosis in bladder cancer cells. Based on transcriptomics and metabolomics, GPD1 promotes Ca 2+ influx and apoptosis of tumor cells via the lysoPC-PAFR-TRPV2 axis. Finally, we performed a virtual screening to obtain the GPD1 allosteric activator wedelolactone and demonstrated its ability to inhibit bladder tumor growth in vitro and in vivo . Conclusions This study suggests that GPD1 may act as a novel tumor suppressor in bladder cancer. Pharmacological activation of GPD1 is a potential therapeutic approach for bladder cancer.
Evidence for Step Therapy in Diabetic Macular Edema
Authors: David C. Musch, Emily Y. Chew
Journal: New England Journal of Medicine (2022)

Step therapy is a treatment approach often required by health insurers to control costs. It involves treating first with a lower-cost medication and, only if that proves ineffective, switching to another, more costly medication. Although step therapy is commonly applied in treating hypertension, diabetes, cancer, and other conditions, concerns regarding its potential for long-term harm to the patient have led some to view it as "fail first" therapy.1,2 One valid criticism of step therapy is a lack of an evidence base for its efficacy and safety. In this issue of the Journal, Jhaveri, Glassman, and colleagues3 describe a rigorous trial . . .
Letter to the editor: Change in serial liver stiffness measurement by magnetic resonance elastography and outcomes in NAFLD
Authors: Georg Semmler, Katrine Holtz Thorhauge, Thomas Reiberger, Maja Thiele
Journal: Hepatology (2022)

To the editor, We read with interest the study by Gidener et al.1 on the value of repeated liver stiffness measurements (LSMs) by magnetic resonance elastography (MRE) for prediction of outcomes in NAFLD. We congratulate the researchers on their statistically sound approach to capture dynamics in LSM and would like to discuss some important aspects of this study. First, the lack of knowledge on the reason for repeating the MRE‐LSM combined with the retrospective design of the study may have introduced selection, confirmation, and survival bias. For example, there is no knowledge of the clinical reason for repeating the MRE measurement, making those selected for and/or survived to have a second LSM an indeed selected cohort. Also, no data on the total number of NAFLD patients who were potentially eligible for a repeated MRE‐LSM are given. With this regard, an inception cohort would allow to compare the prognostic ability of baseline MRE‐LSM with serial changes. Second, the small sample size limits generalizability of the results: The 100% rate of hepatic decompensation was derived from 3 patients from a total of only 29 patients with compensated cirrhosis at last MRE‐LSM, including 2 patients who developed jaundice as an incident event. Similarly, associations of progression with "incident cirrhosis" were derived from 1 in 7 progressors who did not have cirrhosis at last MRE‐LSM. It could be suspected that patients with increasing LSMs are more likely to undergo further investigations and thereby get diagnosed with "incidence cirrhosis." Therefore, larger studies are needed to validate the relevance of "progression" that go beyond the 19% increase cutoff. Although this cutoff has been derived from the repeatability coefficient in MRE2 and was proposed to be corresponding to a "true" change in LSM, its clinical significance remains to be validated. Third, whereas only hypertension was associated with changes in LSM, further elaboration/discussion of this finding could limit speculations about unmeasured confounders given the limited pathophysiological evidence for a causal connection between arterial hypertension and fibrosis progression. Fourth, although the researchers assessed longitudinal changes of MRE‐LSM in NAFLD, it would be interesting to see the results of the subgroup of patients with steatohepatitis being prone to fibrosis progression and liver‐related outcomes. Also, 24 patients with decompensated cirrhosis were included in this study, but neither separately analyzed nor further discussed. Finally, although MRE‐LSM showed a higher accuracy for fibrosis staging compared to vibration‐controlled transient elastography (VCTE), current guidelines do not recommend its routine nor repeated use because of limited availability and unfavorable cost‐effectiveness. With this regard, similar studies investigating the prognostic relevance of dynamics in VCTE‐based LSM are warranted.
Genome-wide meta-analysis of insomnia prioritizes genes associated with metabolic and psychiatric pathways
Authors: Kyoko Watanabe, Philip R. Jansen, Jeanne E. Savage, Priyanka Nandakumar, Xin Wang, Michelle Agee, Stella Aslibekyan, Adam Auton, Robert K. Bell, Katarzyna Bryc, Sarah K. Clark, Sarah L. Elson, Kipper Fletez-Brant, Pierre Fontanillas, Nicholas A. Furlotte, Pooja M. Gandhi, Karl Heilbron, Barry Hicks, Karen E. Huber, Ethan M. Jewett, Yunxuan Jiang, Aaron Kleinman, Keng-Han Lin, Nadia K. Litterman, Jennifer C. McCreight, Matthew H. McIntyre, Kimberly F. McManus, Joanna L. Mountain, Sahar V. Mozaffari, Elizabeth S. Noblin, Carrie A. M. Northover, Jared O’Connell, Steven J. Pitts, G. David Poznik, J. Fah Sathirapongsasuti, Janie F. Shelton, Jing Shi, Suyash Shringarpure, Chao Tian, Joyce Y. Tung, Robert J. Tunney, Vladimir Vacic, Wei Wang, David A. Hinds, Joel Gelernter, Daniel F. Levey, Renato Polimanti, Murray B. Stein, Eus J. W. Van Someren, August B. Smit, Danielle Posthuma
Journal: Nature Genetics (2022)
Histone demethylase JMJD3 downregulation protects against aberrant force-induced osteoarthritis through epigenetic control of NR4A1
Authors: Yu Jin, Zhen Liu, Zhenxia Li, Hairui Li, Cheng Zhu, Ruomei Li, Ting Zhou, Bing Fang
Journal: International Journal of Oral Science (2022)

Abstract Osteoarthritis (OA) is a prevalent joint disease with no effective treatment strategies. Aberrant mechanical stimuli was demonstrated to be an essential factor for OA pathogenesis. Although multiple studies have detected potential regulatory mechanisms underlying OA and have concentrated on developing novel treatment strategies, the epigenetic control of OA remains unclear. Histone demethylase JMJD3 has been reported to mediate multiple physiological and pathological processes, including cell differentiation, proliferation, autophagy, and apoptosis. However, the regulation of JMJD3 in aberrant force-related OA and its mediatory effect on disease progression are still unknown. In this work, we confirmed the upregulation of JMJD3 in aberrant force-induced cartilage injury in vitro and in vivo. Functionally, inhibition of JMJD3 by its inhibitor, GSK-J4, or downregulation of JMJD3 by adenovirus infection of sh-JMJD3 could alleviate the aberrant force-induced chondrocyte injury. Mechanistic investigation illustrated that aberrant force induces JMJD3 expression and then demethylates H3K27me3 at the NR4A1 promoter to promote its expression. Further experiments indicated that NR4A1 can regulate chondrocyte apoptosis, cartilage degeneration, extracellular matrix degradation, and inflammatory responses. In vivo, anterior cruciate ligament transection (ACLT) was performed to construct an OA model, and the therapeutic effect of GSK-J4 was validated. More importantly, we adopted a peptide-siRNA nanoplatform to deliver si-JMJD3 into articular cartilage, and the severity of joint degeneration was remarkably mitigated. Taken together, our findings demonstrated that JMJD3 is flow-responsive and epigenetically regulates OA progression. Our work provides evidences for JMJD3 inhibition as an innovative epigenetic therapy approach for joint diseases by utilizing p5RHH-siRNA nanocomplexes.
Association of vancomycin plus piperacillin–tazobactam with early changes in creatinine versus cystatin C in critically ill adults: a prospective cohort study
Authors: Todd A. Miano, Sean Hennessy, Wei Yang, Thomas G. Dunn, Ariel R. Weisman, Oluwatosin Oniyide, Roseline S. Agyekum, Alexandra P. Turner, Caroline A. G. Ittner, Brian J. Anderson, F. Perry Wilson, Raymond Townsend, John P. Reilly, Heather M. Giannini, Christopher V. Cosgriff, Tiffanie K. Jones, Nuala J. Meyer, Michael G. S. Shashaty
Journal: Intensive Care Medicine (2022)

Although dozens of studies have associated vancomycin + piperacillin-tazobactam with increased acute kidney injury (AKI) risk, it is unclear whether the association represents true injury or a pseudotoxicity characterized by isolated effects on creatinine secretion. We tested this hypothesis by contrasting changes in creatinine concentration after antibiotic initiation with changes in cystatin C concentration, a kidney biomarker unaffected by tubular secretion.
SARS-CoV-2–specific T cells in unexposed adults display broad trafficking potential and cross-react with commensal antigens
Authors: Laurent Bartolo, Sumbul Afroz, Yi-Gen Pan, Ruozhang Xu, Lea Williams, Chin-Fang Lin, Ceylan Tanes, Kyle Bittinger, Elliot S. Friedman, Phyllis A. Gimotty, Gary D. Wu, Laura F. Su
Journal: Science Immunology (2022)

The baseline composition of T cells directly affects later response to pathogens, but the complexity of precursor states remains poorly defined. Here, we examined the baseline state of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells in unexposed individuals. SARS-CoV-2-specific CD4+ T cells were identified in prepandemic blood samples by major histocompatibility complex (MHC) class II tetramer staining and enrichment. Our data revealed a substantial number of SARS-CoV-2-specific T cells that expressed memory phenotype markers. Integrated phenotypic analyses demonstrated diverse preexisting memory states that included cells with distinct polarization features and trafficking potential to barrier tissues. T cell clones generated from tetramer-labeled cells cross-reacted with antigens from commensal bacteria in the skin and gastrointestinal tract. Direct ex vivo tetramer staining for one spike-specific population showed a similar level of cross-reactivity to sequences from endemic coronavirus and commensal bacteria. These data highlight the complexity of precursor T cell repertoire and implicate noninfectious exposures to common microbes as a key factor that shapes human preexisting immunity to SARS-CoV-2.
Errors in Figure 2
Journal: JAMA Oncology (2022)

Elizabeth C. Smyth, MB, BCh, MSc; Andrew Wotherspoon, MD; Clare Peckitt, MSc; David Gonzalez, PhD; Sanna Hulkki-Wilson, BSc, MSc; Zakaria Eltahir, PhD; Matteo Fassan, MD, PhD; Massimo Rugge, MD, FACG; Nicola Valeri, MD, PhD; Alicia Okines, MD; Madeleine Hewish, MD, PhD; William Allum, MD; Sally Stenning, MSc; Matthew Nankivell, MSc; Ruth Langley, MD, PhD; David Cunningham, MD, FMedSci
Mapping and targeted viral activation of pancreatic nerves in mice reveal their roles in the regulation of glucose metabolism
Authors: M. Jimenez-Gonzalez, R. Li, L. E. Pomeranz, A. Alvarsson, R. Marongiu, R. F. Hampton, M. G. Kaplitt, R. C. Vasavada, G. J. Schwartz, S. A. Stanley
Journal: Nature Biomedical Engineering (2022)
Setting the Benchmark for <i> KRAS <sup>G12C</sup> </i> -Mutated NSCLC
Authors: Antonio Passaro, Solange Peters
Journal: New England Journal of Medicine (2022)

Activating mutations in the KRAS proto-oncogene were identified and characterized more than 40 years ago across several distinct human cancers, including pancreatic and colorectal cancers as well as non–small-cell lung cancer (NSCLC). KRAS somatic alterations are found in approximately 25 to 30% of lung adenocarcinomas and represent the most prevalent genomic driver event in NSCLC.1 Within KRAS variants in NSCLC, the KRAS p.G12C single-nucleotide mutation (glycine-to-cysteine substitution at codon 12) is found in approximately 13% of lung adenocarcinomas. KRAS-mutated NSCLCs are generally associated with smoking (current or former use), increased programmed death ligand 1 (PD-L1) expression on tumor cells, an . . .
Frequent detection but lack of infectivity of SARS-CoV-2 RNA in presymptomatic, infected blood donor plasma
Authors: Paula Saá, Rebecca V. Fink, Sonia Bakkour, Jing Jin, Graham Simmons, Marcus O. Muench, Hina Dawar, Clara Di Germanio, Alvin J. Hui, David J. Wright, David E. Krysztof, Steven H. Kleinman, Angela Cheung, Theresa Nester, Debra A. Kessler, Rebecca L. Townsend, Bryan R. Spencer, Hany Kamel, Jacquelyn M. Vannoy, Honey Dave, Michael P. Busch, Susan L. Stramer, Mars Stone, Rachael P. Jackman, Philip J. Norris
Journal: Journal of Clinical Investigation (2022)

Respiratory viruses such as influenza do not typically cause viremia; however, SARS-CoV-2 has been detected in the blood of COVID-19 patients with mild and severe symptoms. Detection of SARS-CoV-2 in blood raises questions about its role in pathogenesis as well as transfusion safety concerns. Blood donor reports of symptoms or a diagnosis of COVID-19 after donation (post-donation information, PDI) preceded or coincided with increased general population COVID-19 mortality. Plasma samples from 2,250 blood donors who reported possible COVID-19-related PDI were tested for the presence of SARS-CoV-2 RNA. Detection of RNAemia peaked at 9%-15% of PDI donors in late 2020 to early 2021 and fell to approximately 4% after implementation of widespread vaccination in the population. RNAemic donors were 1.2- to 1.4-fold more likely to report cough or shortness of breath and 1.8-fold more likely to report change in taste or smell compared with infected donors without detectable RNAemia. No infectious virus was detected in plasma from RNAemic donors; inoculation of permissive cell lines produced less than 0.7-7 plaque-forming units (PFU)/mL and in susceptible mice less than 100 PFU/mL in RNA-positive plasma based on limits of detection in these models. These findings suggest that blood transfusions are highly unlikely to transmit SARS-CoV-2 infection.
Mural Cell SRF Controls Pericyte Migration, Vessel Patterning and Blood Flow
Authors: Michael M. Orlich, Rodrigo Diéguez-Hurtado, Regine Muehlfriedel, Vithiyanjali Sothilingam, Hartwig Wolburg, Cansu Ebru Oender, Pascal Woelffing, Christer Betsholtz, Konstantin Gaengel, Mathias Seeliger, Ralf H. Adams, Alfred Nordheim
Journal: Circulation Research (2022)

Pericytes and vascular smooth muscle cells, collectively known as mural cells, are recruited through PDGFB (platelet-derived growth factor B)-PDGFRB (platelet-derived growth factor receptor beta) signaling. MCs are essential for vascular integrity, and their loss has been associated with numerous diseases. Most of this knowledge is based on studies in which MCs are insufficiently recruited or fully absent upon inducible ablation. In contrast, little is known about the physiological consequences that result from impairment of specific MC functions. Here, we characterize the role of the transcription factor SRF (serum response factor) in MCs and study its function in developmental and pathological contexts.We generated a mouse model of MC-specific inducible Srf gene deletion and studied its consequences during retinal angiogenesis using RNA-sequencing, immunohistology, in vivo live imaging, and in vitro techniques.By postnatal day 6, pericytes lacking SRF were morphologically abnormal and failed to properly comigrate with angiogenic sprouts. As a consequence, pericyte-deficient vessels at the retinal sprouting front became dilated and leaky. By postnatal day 12, also the vascular smooth muscle cells had lost SRF, which coincided with the formation of pathological arteriovenous shunts. Mechanistically, we show that PDGFB-dependent SRF activation is mediated via MRTF (myocardin-related transcription factor) cofactors. We further show that MRTF-SRF signaling promotes pathological pericyte activation during ischemic retinopathy. RNA-sequencing, immunohistology, in vivo live imaging, and in vitro experiments demonstrated that SRF regulates expression of contractile SMC proteins essential to maintain the vascular tone.SRF is crucial for distinct functions in pericytes and vascular smooth muscle cells. SRF directs pericyte migration downstream of PDGFRB signaling and mediates pathological pericyte activation during ischemic retinopathy. In vascular smooth muscle cells, SRF is essential for expression of the contractile machinery, and its deletion triggers formation of arteriovenous shunts. These essential roles in physiological and pathological contexts provide a rationale for novel therapeutic approaches through targeting SRF activity in MCs.
Inherited Germline Cancer Susceptibility Gene Variants in Individuals with Non–Muscle-Invasive Bladder Cancer
Authors: Eugene J. Pietzak, Karissa Whiting, Preethi Srinivasan, Chaitanya Bandlamudi, Aliya Khurram, Vijai Joseph, Aleksandra Walasek, Emily Bochner, Timothy Clinton, Nima Almassi, Hong Truong, Manuel R. de Jesus Escano, Michal Wiseman, Diana Mandelker, Yelena Kemel, Liying Zhang, Michael F. Walsh, Karen A. Cadoo, Jonathan A. Coleman, Hikmat Al-Ahmadie, Jonathan E. Rosenberg, Gopakumar V. Iyer, David B. Solit, Irina Ostrovnaya, Kenneth Offit, Mark E. Robson, Zsofia K. Stadler, Michael F. Berger, Dean F. Bajorin, Maria Carlo, Bernard H. Bochner
Journal: Clinical Cancer Research (2022)

Identification of inherited germline variants can guide personalized cancer screening, prevention, and treatment. Pathogenic and likely pathogenic (P/LP) germline variants in cancer predisposition genes are frequent among patients with locally advanced or metastatic urothelial carcinoma, but their prevalence and significance in patients with non-muscle-invasive bladder cancer (NMIBC), the most common form of urothelial carcinoma, is understudied.
Making Electronic Health Records Both SAFER and SMARTER
Authors: Kevin B. Johnson, William W. Stead
Journal: JAMA (2022)

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